Method for the production of a form of administration of a medicament

ABSTRACT

The present invention relates to a method for producing a medicament dosage form which consists of at least one piece which in each case comprises at least one medicament and at least one additive, the medicament and the additive being mixed and extruded from a die as a strand and the strand being cut into pieces of precise weight. The invention additionally relates to a device.

This application is a divisional of U.S. patent application Ser. No.12/627,591, filed Nov. 30, 2009, now issued as U.S. Pat. No. 8,939,748,which is a continuation of International Patent Application No.PCT/EP2008/004193, filed May 27, 2008, which claims foreign prioritybenefit under 35 U.S.C. § 119 of the German Patent Application No. 102007 025 858.7, filed Jun. 1, 2007, the entire contents of which patentapplications are incorporated herein by reference.

The present invention relates to a method for producing a medicamentdosage form which consists of at least one piece which in each casecomprises at least one medicament and at least one additive, themedicament and the additive being mixed and extruded from a die as astrand.

Such production methods for medicaments are known from the prior art,for example DE 69 509 671 T3. This patent describes a method in whichmedicament and additives are mixed and kneaded in an extruder and theresultant product is then extruded from an extruder die as a strand.This strand is divided into separate pieces. Further processing of thesepieces to yield a finished medicament dosage form is comparativelycomplex, however. It is additionally known according to the prior art toproduce doses of solid dosage forms such as tablets or capsules byweighing.

The object of the present invention was accordingly to provide a methodfor producing a medicament dosage form which does not exhibit thedisadvantages of the prior art.

The object is achieved by a method for producing a medicament dosageform which consists of at least one piece which in each case comprisesat least one medicament and at least one additive, the medicament andthe additive being mixed and extruded from a die as a strand and thestrand being cut into pieces of precise weight.

It was extremely surprising and unexpected for the person skilled in theart that the method is suitable in particular for producingabuse-protected medicament forms. Using the method according to theinvention, it is possible to produce medicament dosage forms veryefficiently. Because the particles are cut into pieces of preciseweight, a medicament dosage form, for example a tablet, may be presseddirectly therefrom or another medicament dosage form produced. Nofurther method step is taken for compliance with the desired weight.

The method according to the invention is suitable for producing amedicament dosage form such as for example a tablet or amultiparticulate dosage form, which comprises granules or pellets, aswell as a suppository. Moreover, using the method according to theinvention, it is possible to produce small cut pieces which may then,for example, be packaged in capsules.

According to the invention this medicament dosage form consists of atleast one piece, which comprises both a medicament and an additive. Inthe case of a tablet, for example, just one piece may be cut from thestrand and then press-moulded to form a tablet. This piece haspreviously in each case been severed from the strand precisely withregard to weight. The tablet may however also comprise a plurality ofrelatively small pieces. These pieces have previously in each case beensevered from the strand precisely with regard to weight. Amultiparticulate dosage form will always comprise a plurality of pieces,which have previously been severed from the strand precisely with regardto weight. These pieces are then introduced into a capsule or into adrinking straw or the like.

According to the invention, each one of the pieces comprises at leastone medicament and at least one additive. A medicament for the purposesof the invention comprises an active ingredient. Analgesics may here bementioned purely by way of example. The additives may be any additivesknown to a person skilled in the art, such as for example fillers,binders and controlled-release matrices. In particular, however, theadditive comprises a substance with which abuse of the medicament may beprevented.

In addition, the medicament dosage form may also comprise vitamins,foodstuffs and/or nutritional supplements.

According to the invention, the mixture of medicament and additives ispreferably homogeneously mixed and particularly preferably transformedinto an extrudable mass by exposure to shear forces and heat. Thisprocess is preferably performed in an extruder familiar to a personskilled in the art. Then the pasty mixture of medicament and additive isextruded from a die as a strand.

According to the invention, after extrusion, this strand is cut intopieces of precise weight, i.e. is divided into pieces of precise weight.For the purposes of the invention, “of precise weight” means that thepiece(s) from which the medicament dosage form is ultimately produceddisplays the admissible weight tolerances.

The length to be severed from the strand is determined for this purposeas follows. The cross-sectional area of the strand prior to cutting tolength has to be known. This may be determined in particular on thebasis of empirical values or on the basis of measurements, for exampleof the diameter. In very rare cases, the strand cross-sectioncorresponds to the cross-section of the die. The quantity of activeingredient may be calculated for a specific unit length on the basis ofthe cross-sectional area and the concentration of active ingredient inthe strand. The length to be severed from the strand is obtained fromthe total desired quantity of active ingredient divided by the quantityof active ingredient per unit length. If the cross-sectional area ismeasured, this may be taken into account when determining the quantityof active ingredient per unit length.

Using the method according to the invention, it is possible to producedosage forms reliably and reproducibly which for example satisfy therequirements of the German Drug Law, the German Ordinance on theManufacture of Drugs and Active Pharmaceutical Ingredients and/or theGerman or European Pharmacopoeia.

The strand is preferably cooled before being cut to length. Preferablythe strand is cooled for long enough to ensure that it does not smearwhen being cut; i.e. comprise bevels, deformations, stringiness and/orthe like, and/or that during cutting no product remains attached to therespective cutting tool, which would impair weight precision. On theother hand, the product should not be cooled to such an extent that therespective cutting tool is damaged or becomes too rapidly blunt. In aparticularly preferred embodiment the strand exhibits high extrudaterigidity or dimensional stability, such that the strand does not becomedeformed under its own weight relative to the extruded cross-section;for example a circle does not become an oval through the action of shearforce.

In a preferred embodiment an electric charge is applied to the cuttingtool, which corresponds to the charge of the strand material. In thisway, the strand material is repelled by the cutting tool, such thatcutting forces are reduced and adhesions to the cutting tool areprevented. This increases the weight precision of the pieces and theservice life of the cutting tool.

It is additionally preferable for the cross-section of the strand to becalibrated prior to cutting to length. In this way, the respectivecross-section of the strand may be reduced to a desired size and/orvariations in cross-section of the strand may be compensated. The strandthen comprises a very exact, uniform cross-sectional area, which in turnincreases weight precision or optionally makes cross-sectionalmeasurements unnecessary. As a result of this preferred embodiment,pieces for the respective medicament dosage form may be producedparticularly precisely with regard to weight.

Preferably, the strand is drawn out at a specific speed by a drawingdevice prior to being cut to length. This preferred embodiment of themethod according to the invention has the advantage that the speed withwhich the strand is conveyed is known. This speed does not have to beconstant but preferably is so. Preferably, the drawing device is adevice in which at most slight slip arises between the device and thestrand to be drawn out. Preferably, the drawing device is a“caterpillar” drawing device, in which two caterpillars are rotated inopposite directions from one another and thereby convey the strand in agiven direction. Preferably, the strand is here somewhat gripped betweenthe caterpillars. Preferably, the drive devices are driven by a drivewhich outputs a signal with which the draw-out speed may be determined.The drive may for example be a motor with a transducer, for example aservomotor.

The rate of production of the strand and the speed of the drawing deviceshould be substantially identical, some strand material advantageouslyalways being buffered upstream of the drawing device to prevent thestrand from being subjected to unnecessary tensile load and thuschanging its cross-section. The buffering may proceed for example by wayof a simple loop. Accordingly, the speed of the drawing device may beused to regulate the entire procedure.

In a particularly preferred embodiment, the strand is drawn from theextruder by a first drawing device, then guided into a buffering loopand thereafter supplied to the cutting device by means of a seconddrawing device.

Particularly preferably, the signal from this drive is used to regulatethe cutting device which cuts the strand into individual piecesprecisely with regard to weight. Regulation proceeds in such a way thatcutting always takes place when the volume to be cut off has beenconveyed past the cutting tool. With a constant strand cross-section,the strand is conveyed a certain distance past the cutting device beforecutting takes place.

Preferably, this cutting device is a rotating cutting device, forexample one or more rotating blades with which the strand is cut offcyclically. Possible blades are a simple rotating blade, acrescent-shaped blade or a circular blade. Preferably, the blade(s)is/are driven by a servomotor.

Other possible cutting apparatuses are based on radiation.

Cutting to length preferably proceeds with ongoing feed of the strand.

Preferably, the strand is guided during cutting to length, this guidancebeing effected for example by a sleeve, which at least partiallyencloses the cross-section of the strand and acts as a steady for thecutting device. Particularly preferably, both the piece to be cut offand also the remaining strand are guided. This allows a particularlyexact cut to be achieved. The guide may take the form for example of twoseparate sleeves, which exhibit a somewhat larger cross-section than thestrand to be cut to length. One sleeve is located upstream of thecutting device in the direction of travel of the strand and onedownstream of the cutting device. The cutting device enters the gapbetween the sleeves.

Preferably, the guide comprises temperature control, which makes itpossible to change the temperature of the strand once more beforecutting to length.

Preferably, the cut-off pieces are singulated after being cut to length.This is effected in particular by mechanical energy such as for exampleby an airstream, which singulates the cut-off pieces.

Preferably, the constant production of pieces is monitored. This maytake place for example by means of a sensor at the outlet of the cuttingdevice. As soon as this sensor ceases to detect any more cut-off pieces,the procedure is preferably interrupted.

The method according to the invention is suitable for the production ofany medicament dosage form. However, it is particularly suitable formedicaments which are abuse-protected and which are disclosed forexample in DE 103 36 400.5, DE 103 61 596.2, DE 10 2004 020 220.6, DE 102004 032 049.7, DE 10 2004 032 103.5, DE 10 2004 032 051.9, DE 10 2005005 446.3, DE 10 2005 005 449.8 and DE 10 2007 011 485.2. These patentapplications are hereby introduced as references and are accordinglydeemed to be part of the disclosure.

The present invention also provides a device for cutting a strand intopieces of a precise weight, said strand being extruded from a die, whichdevice has a means for cutting the strand to length and comprises ameans for calibrating the cross-section of the strand.

The entire disclosure made in relation to the method according to theinvention applies equally to the device according to the invention.

It is possible, with the device according to the invention, to cut astrand into pieces of a precise weight.

For the purposes of the invention “of precise weight” means that theactual weight of the severed pieces complies with the German Drug Law,the German Ordinance on the Manufacture of Drugs and ActivePharmaceutical Ingredients and/or the German or European Pharmacopoeia.

According to the invention, the device comprises calibration, with whichthe cross-section of the strand is shaped to a desired value. Cooling ispreferably arranged upstream of the calibration, which cools the strandto the extent that it remains in the calibrated form after calibrationand undergoes no further or no appreciable change.

Preferably, the device according to the invention comprises a means fordrawing out the strand. With this means it is possible to convey thestrand at a specific speed, which does not have to be constant but ispreferably constant. Preferably this drive means comprises a drive whichoutputs a signal with which the draw-out speed may be determined.Preferably the means comprises drawing “caterpillars”, which arearranged opposite one another across the strand cross-section. Theseadjustable caterpillars exhibit no or only very slight slip relative tothe strand, such that the speed of rotation of the rollers correspondsto the conveying speed of the strand. Preferably the caterpillars may bepretensioned against the strand and/or are adaptable to differentcross-sections. Preferably, the conveying means comprises a drive whichoutputs a signal with which said draw-out speed may be determined.

Preferably, the device comprises a first draw-out means for drawing thestrand out of the extruder, a buffering loop and a second draw-out meansfor feeding the strand to the cutting device.

Preferably, the device according to the invention additionally comprisesa control unit which receives the signal output by the drive andpreferably controls the cutting device, with which the strand is cut tolength, with this signal. Furthermore, the rate at which the strand isproduced is also regulated by means of the draw-out speed.

Preferably, this cutting device comprises a rotating blade. In thispreferred embodiment the rotational speed of the blade is regulated bythe device.

It is also preferable for the strand to be guided during cutting. Thisguidance is provided for example by a guide sleeve, which at leastpartially encloses the strand.

Preferably, both the piece to be cut off and the remaining strand areguided, so allowing particularly precise cutting.

In a further preferred embodiment, the temperature of the strand may beadjusted after draw-out and before cutting to length, in order toestablish an ideal strand temperature for cutting to length.

BRIEF DESCRIPTION OF THE DRAWING

The invention will be explained in greater detail below with referenceto the drawing, wherein:

FIG. 1 is a process schematic showing one possible embodiment of themethod according to the invention or the device according to theinvention.

These explanations are given merely by way of example and do notrestrict the general concept of the invention. These explanations applyequally to both the method according to the invention and the deviceaccording to the invention.

FIG. 1 shows a possible embodiment of the method according to theinvention or the device according to the invention. The extruder 1 isfilled continuously with a medicament 8 and an additive 10. These may bepresent separately or in a mixture and also do not have to be added tothe extruder at the same point. In the extruder, the medicament and theadditive are processed with exposure to heat and shear forces into ahomogeneous pasty mass. This mass is extruded continuously using the die11 into a strand 2. The cross-sectional shape of the strand depends forexample on the shape of the tablet to be produced subsequently. Saidstrand 2 is firstly cooled in a cooler 3 from the extrusion temperatureto a lower temperature, which amounts to approx. 55-45% of the extrusiontemperature. Between the extruder die 11 and the cooler 3, the strand 2preferably comprises a loop (not shown) of adjustable size as a buffer.Inside the cooler there is located for example an endless conveyor belt,which conveys the strand 2 through the cooler. The strand may also liein loops on this conveyor belt, in order to reduce the length of thecooler and/or the transit time. After cooling, the strand 2 ispreferably calibrated. In this case, the strand cross-section is reducedto a cross-section which is substantially uniform over the length of thestrand. Preferably, calibration involves at least one pair of rolls,which are arranged at a given distance from one another. The strand isguided through the respective pair of rolls and reduced in cross-sectionin the process. The rolls are driven synchronously and are optionallytemperature-controllable. After calibration, the cross-section of thestrand is preferably measured. Measurement is effected using a pluralityof lasers. The result of this measurement may be used to control thecutting device 7. Downstream of the calibration stage a drawing device 5is arranged in the form of two caterpillars of adjustable spacing, thelower caterpillar rotating clockwise and the upper caterpillar rotatinganticlockwise. The caterpillars are driven by a servomotor, whichoutputs a signal with which the speed of rotation and thus the draw-outspeed of the strand may be determined. The speed of the caterpillars isadjustable and does not have to be constant. The caterpillars arelightly pretensioned against the strand, in order as far as possible toavoid slip. The caterpillar drive signal is supplied to a controller, asshown by the broken line, which controller controls the cutting device.On the basis of the concentration (mg/volume) of the active ingredientin the strand and the knowledge of the cross-sectional area aftercalibration, the controller calculates the length of the strand in eachcase to be severed, in order to obtain a medicament dosage form or apiece of a given medicament dosage form with a specific quantity ofactive ingredient. On the basis of the conveying speed, the time mayaccordingly be calculated at which severing of the respective piece musttake place. Severing is effected by means of a severing device, in thepresent case a rotatingly driven blade holder on which are arranged one,two or more blades. The controller then controls the rotational speed ofthe blade holder in such a way that pieces of precise weight are cut.The controller here takes account in any case of the conveying speed ofthe strand and optionally also of the result of diameter measurementupstream of the drawing device, in particular when the cross-section ofthe strand varies greatly over the length thereof. During cutting, thestrand is guided in a sleeve, whose cross-section is somewhat largerthan the cross-section of the strand. The sleeve guides the strandupstream and downstream of the cutting device. The temperature of saidsleeve is adjusted with a liquid in order to be able optionally to heator cool the strand once again prior to cutting. For this purpose,temperature measurement is arranged upstream of the sleeve, measuringthe surface temperature of the strand in a contactless manner. Thetemperature of the strand should be such that the longest possible bladeservice life and in each case a clean cut without residues anddeformation is ensured. Preferably, the strand is accordingly cut tolength by means of the severing device not only by cutting but also bybeing knocked off. Downstream of the cutting device a tubular guide isalso arranged, which singulates the severed pieces. A sensor arranged inor upstream of this area permanently detects whether pieces 9 are beingsevered and stops the production process if this is not the case. Aftercutting to length, the pieces 9 of precise weight which are produced arecollected in a buffer means and then arrive, if shaping is desired, at apress, in which they are given their final shape. It is also possible,however, for a plurality of pieces to be processed into a medicamentdosage form. In this case, the desired number are combined and thenfurther processed. The pieces may be combined on a purely numericalbasis, since the pieces are of a precise weight and a given number ofpieces thereby also gives rise to the desired quantity of medicament. Inthis way, tablets which are press-moulded from a plurality of pieces ormultiparticulate tablets may be produced.

LIST OF REFERENCE NUMERALS

1 Extruder

2 Strand

3 Cooling

4 Calibration

5 Drawing device, caterpillar drawing device

6 Signal

7 Cutting device

8 Medicament

9 Severed pieces

10 Additives

11 Die

The invention claimed is:
 1. A method for producing a medicament dosageform which consists of one or more pieces which in each case comprisesat least one medicament and at least one additive, said methodcomprising (i) mixing the at least one medicament and the at least oneadditive to form a pasty mixture, (ii) extruding an extrudate consistingof the pasty mixture from a die as a strand, (iii) calibrating across-section of the strand, and thereafter (iv) measuring thecross-section of the strand, (v) determining a cross-sectional area ofthe strand, (vi) calculating a length of the strand to be severed on abasis of a concentration of an active ingredient in the strand and thecross-sectional area determined after the calibrating of thecross-section of the strand, (vii) cutting the strand into one or morepieces of said length and, as a result, predetermined weight, and (viii)producing said medicament dosage form directly from said one or morepieces of said length without further steps being taken for compliancewith the predetermined weight.
 2. A method according to claim 1, whereinthe strand is cooled prior to cutting to length.
 3. A method accordingto claim 1, wherein the calibrating proceeds after cooling.
 4. A methodaccording to claim 1, which further comprises, prior to cutting tolength, drawing out the strand at a predetermined speed using a drawingdevice.
 5. A method according to claim 4, which further comprisesbuffering the strand prior to the drawing out.
 6. A method according toclaim 4, which further comprises outputting a signal by the drawingdevice, determining the draw-out speed with said signal, and using saiddraw-out speed to control a cutting device with which the strand is cutto length.
 7. A method according to claim 1, wherein said cutting tolength is effected by a rotating cutting device.
 8. A method accordingto claim 7, wherein a conveying speed regulates a rotational speed ofthe cutting device.
 9. A method according to claim 1, wherein the strandis guided during cutting to length.
 10. A method according to claim 1,which further comprises checking a diameter of the strand prior tocutting to length.
 11. A method according to claim 1, which furthercomprises singulating the pieces after cutting to length.
 12. A methodaccording to claim 1, which further comprises adjusting a temperature ofthe strand once more after drawing out and before cutting to length. 13.A method for producing a medicament dosage form, said dosage formconsisting of one or more pieces, said one or more pieces comprising atleast one medicament and at least one additive, said method comprising(i) mixing the at least one medicament and the at least one additive toform a mixture, (ii) extruding the mixture from a die as a strand, (iii)buffering the strand between a first and a second drawing out means,(iv) calibrating a cross-section of the strand, and thereafter (v)measuring the cross-section of the strand, (vi) determining across-sectional area of the strand, (vii) calculating a length of thestrand to be severed on a basis of a concentration of an activeingredient in the strand and the cross-sectional area determined afterthe calibrating of the cross-section of the strand, (viii) cutting thedrawn out strand into one or more pieces of said length and, as aresult, predetermined weight, and (ix) producing the medicament dosageform directly from said one or more pieces without further steps beingtaken for compliance with the predetermined weight.
 14. A methodaccording claim 1, wherein said pasty mixture is homogeneous.